Where We Go from Here in the Management of Multiple Sclerosis

PERSPECTIVES IN MS

Beyond Efficacy and Safety: Where We Go From Here in the Management of Multiple Sclerosis

Introduction radiologically isolated syndrome (RIS) who are at high When selecting a disease-modifying therapy (DMT) for risk for the development of clinically definite MS (CDMS) patients with multiple sclerosis (MS), clinicians must first should also be treated with DMTs as soon as possible. consider the efficacy and safety of the agent.1 Other consid- Several clinical trials have provided proof of concept for erations include initiating treatment as early as possible, an early window of initial treatment intervention in patients adherence to current and subsequent DMTs, under- with CIS.9 Significant reductions in the risk for developing standing when to switch patients from their current DMTs CDMS were observed with the use of interferon beta agents to other medications (and knowing when not to switch), and glatiramer acetate when treatment was initiated early and cost factors.2-5 on. Physical disability and number and/or volume of brain Although the currently approved DMTs are reliable, lesions were also improved with early treatment. Similar constantly being improved, effective in treating relapses, results have been reported with some of the newer DMTs, and able to reduce long-term disability, they have only such as teriflunomide, alemtuzumab, and fingolimod. limited efficacy in treating progressive disease that is not associated with inflammatory relapses.6 More effective Adherence to Disease-Modifying Therapies DMTs are needed specifically for patients with primary According to the World Health Organization (WHO), progressive MS. Likewise, agents that repair or regenerate adherence is defined as “the extent to which a person’s neurons, oligodendrocytes, and supporting glia are essen- behavior—taking medication, following a diet, and/or tial for effective treatment.7 executing lifestyle changes— corresponds with agreed Several new medications have entered the market in recommendations from a health care provider.”10,11 There recent years and others are in late-phase clinical studies are 3 distinct components of adherence: (1) acceptance, (2) for the treatment of patients with relapsing or progressive persistence, and (3) compliance.10,12 Patients must accept forms of MS.8 These agents represent a variety of mecha- that they need treatment, they must persist in taking the nisms of action, providing not only lower relapse rates but treatment over time, and they must comply with their also improvement in disabilities. prescribed treatment (that is, take the right dose at the right time and with the correct frequency). Importance of Early Diagnosis and Early Treatment Medication adherence is a major concern in the MS MS is characterized by both inflammation and progres- population, particularly with DMTs.10,12,13 The WHO sive neuroaxonal damage.9 Although this damage often estimates an average adherence rate of only 50% among occurs in the early stages of disease, it may be masked by compensatory Brain Atrophy Occurs Early in the Disease Process mechanisms. Thus, progressive damage Figure 1. may go unrecognized until it is too late for intervention to be beneficial. As MS progresses, the balance between the degenerative and the reparative processes shifts, resulting in progressive neuroaxonal degeneration and increasing disability (see Figure 1).9 Because brain atrophy creates permanent damage, and correlates with physical and cognitive disability, it is important for patients with MS to be treated with DMTs as early in the disease course as possible, in order to decrease the loss of brain volume and its effects.2 Additionally, patients with Figure reprinted with permission from the Multiple Sclerosis Foundation and EW Associates, LLC. clinically isolated syndrome (CIS) and

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chronically ill patients in the developed Figure 2. The Benefits of Adherence10 world.10,13 Although overall rates of adher- Clinician Benefits ence to DMTs in patients with MS is Lower risk for relapse estimated to be higher than 50%,10,12 varia- Improved QoL tions among studies and medications do Patient Benefits exist. Suboptimal adherence to DMTs has a Lower risk for relapse Better QoL Payer Benefits negative impact on patient morbidity and Higher treatment satisfaction Lower medical costs Fewer hospitalizations Fewer hospitalization mortality outcomes, as well as on overall Fewer ED visits Fewer ED visits costs of patient care.1,10 Some of the major Less work loss benefits associated with patient adherence Societal Benefits to therapy are displayed in Figure 2. Improvements in productivity Four recent studies have evaluated Less work loss due to sick days and disability adherence rates with the first-generation, ED indicates emergency department; QoL, quality of life. injectable DMTs (including interferon beta-1b, intramuscular interferon beta-1a, subcutaneous interferon beta-1a, and glatiramer acetate) (AEs) associated with the agent, and fear/anxiety over using used in the treatment of MS.13-16 injections.10,11 A number of different approaches might help to improve adherence among patients with MS. • In a population-based cohort study of 4830 patients, optimal adherence was observed in 76% of patients • Enlist support from family members and/ after 1 year of therapy.13 Patients who initiated or caregivers.10 therapy in recent years were more likely to have • For patients who experience cognitive impairment suboptimal adherence and to discontinue their DMT and those who frequently forget to take their medi- within the first 12 months versus those who began cation, efforts should be made to simplify treatment treatment in earlier years. regimens.10 Medications that can be adminis- • In a systematic review of medication adherence tered fewer versus more times per day should be from 24 studies with a combined population of suggested, and monotherapy options rather than >2400 patients, 59.6% of patients were adherent to combination therapies should be recommended. therapy.14 Common barriers to adherence included • Establish realistic expectations about the potential patients forgetting to their take medication, benefits of treatment.1,12 Patients should under- perceived lack of efficacy, anxiety about injections, stand that DMTs do not “cure” MS, that they may and adverse reactions. not eliminate MS symptoms, and that they may not • In a multicenter, observational study of 798 completely eradicate future disease activity. patients, nonadherence was reported by 36% to • Evaluate the economic burden on patients associ- 39% of patients surveyed.15 Forgetting to admin- ated with the use of MS medications.10,11 Providers ister their injections, which was the most common should have an improved understanding of formu- reason cited by participants for nonadherence, lary issues, such as the selection of agents that are was reported by 58% of those with adherence available on the formulary, the formulary override issues. Other reasons for nonadherence included process, prior authorization, initiation and ongoing injection-site reactions, effects on quality of life, and approval, and adherence to Risk Evaluation and symptoms of depression. Mitigation Strategies (REMS), where needed.5 • Of the 2648 patients evaluated in the Global Additionally, support from a social worker can be Adherence Project, 75% were adherent to therapy.16 helpful, along with enlisting aid from the manufac- The most common reported reasons for nonadher- turer. Medication assistance programs exist for all of ence included forgetting to administer the injection the FDA-approved DMTs. and other injection-related reasons. Provide injection training for injectable DMTs.10-12 For Adherence is difficult to quantify.10 In many cases, there example, patients should be trained to rotate injection can be multiple contributing factors to poor adherence sites, to use an autoinjector (which is available free of versus only one factor. Clinical trial data have identified a charge from manufacturers), to inject medications at room myriad of contributing factors that lead to poor adherence, temperature, to ice the area before and after injecting including cognitive impairment, perceived lack of efficacy medication, and to massage the area following injection from DMTs, economic/financial challenges, adverse events (for interferon beta products only).

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Manage AEs accordingly.10-12 Remind patients using switching should be considered earlier than later, because interferon beta agents that flulike symptoms often improve residual impairment may worsen with each new relapse. with time, and can be relieved by premedication with It is also important to recognize that switching DMTs may nonsteroidal anti-inflammatory drugs or acetaminophen. lead to breakthrough disease, particularly with longer- The impact of flulike symptoms may also be reduced by acting products. administering the agent in the evening, before bed, on the Other considerations (besides risks/benefits, which weekend, or before another convenient period of time. have been discussed previously) when switching thera- For patients who experience poor treatment adherence pies include the following: immunogenicity; mechanism because of anxiety or fear over administering injections, of action of prior DMTs, which can affect the efficacy and consider switching to an oral therapy.11 safety of subsequent therapies; risk for progressive multi- focal leukoencephalopathy (PML); and immunization Switching Therapies status.1,4 Patients should also be evaluated for active or Patients who do not respond well to one DMT may need uncontrolled infections. to switch to another DMT.1,3,4,17 Possible markers of nonre- The presence of neutralizing antibodies, which is sponse to treatment include continued, frequent relapses associated with several DMTs (including beta interferon or magnetic resonance imaging findings suggestive of medications and natalizumab), can decrease the effective- disease activity (such as gadolinium-enhancing activity ness of an agent and thus can lead to increased disease or new lesion formation).3 Switching therapies also may activity.1,7,19 It is generally not advisable to switch a patient be necessary for patients who experience intolerable who has developed neutralizing antibodies from one inter- adverse events; however, switching treatments within feron beta agent to another, because he or she will likely 6 months of treatment is discouraged, because many also develop neutralizing antibodies from use of the second adverse events diminish over time.12 Switching medications interferon beta agent. might also be indicated for patients who have difficulty A transition period between stopping a current DMT remaining adherent to therapy, as switching is often an and initiating a new DMT may be necessary in some effective method in which to proactively promote medica- circumstances.4 For example, the immunologic effect of tion adherence.11 alemtuzumab (which is not related to its half-life) may Timing is also an important consideration when it persist long after the cessation of treatment. This might comes to switching therapy.1,4,18 If patients are experiencing potentially expose patients to immune-mediated risks disease progression despite being treated with a DMT, when they are switched to other DMTs.

TABLE 1. Annual Costs Associated With the Use of Disease-Modifying Therapies5 Annual Cost at Market Product FDA Approval Date 2017 Annual Cost, $ Introduction, $ Interferon beta-1b (Betaseron) July 1993 10,920 86,421 Interferon beta-1a (Avonex) May 1996 8261 81,731 Glatiramer acetate 20 mg (Copaxone) December 1996 7852 86,554 Interferon beta-1a (Rebif) March 2002 13,875 86,179 Natalizumab (Tysabri) November 2004 23,500 78,000 Interferon beta-1b (Extavia) August 2009 29,842 72,160 Fingolimod (Gilenya) September 2010 48,083 86,966 Teriflunomide (Aubagio) September 2012 45,124 76,612 Dimethyl fumarate (Tecfidera) March 2013 54,750 82,977 Glatiramer acetate 40 mg (Copaxone) January 2014 60,336 75,816 Peginterferon beta-1b (Plegridy) August 2014 62,036 81,731 Alemtuzumab (Lemtrada) November 2014 65,833 69,166 Daclizumab* (Zinbryta) May 2016 82,000 86,838 Ocrelizumab (Ocrevus) March 2017 65,000 65,000

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TABLE 2. Drug Pipeline for Multiple Sclerosis8,30-33,35-42

Agent Description Clinical Development Program

Laquinimod • Orally administered immunomodulator being • Mixed efficacy results have been observed in phase 3 trials studied for the treatment of RRMS and PPMS oo In the ALLERGO trial, ARR, disability progression, and • Although its exact MOA is unknown, number of Gd-enhancing lesions all were improved laquinimod appears to influence the TH1 to significantly with laquinimod versus placebo TH2 cytokine shift oo In the BRAVO trial, ARR was not significantly reduced with laquinimod versus placebo • In the ALLERGO and BRAVO trials, the most commonly reported AEs with laquinimod included elevated LFTs, abdominal pain, back pain, and cough • Phase 3 CONCERTO trial in RRMS has not reported results • Phase 2 ARPEGGIO trial in PPMS has not reported results

Masitinib • Orally administered tyrosine kinase inhibitor • In a pilot study, masitinib appeared to have a positive effect on that targets mast cells and inhibits several MS-related impairment in patients with PPMS and relapse-free biochemical processes SPMS. The most commonly reported AEs included asthenia, • Being studied in PPMS and SPMS rash, nausea, edema, and diarrhea • Phase 3 trial in patients with PPMS or relapse-free SPMS has been halted

Ofatumumab • Depletes B cells via antibody-dependent, • In a phase 2 trial, significantly fewer T1 Gd-enhancing lesions, cell-mediated toxicity and complement- total number of T1 Gd-enhancing lesions, and new or enlarging dependent cytotoxicity T2 lesions were observed with ofatumumab versus placebo. No • Administered intravenously or subcutaneously unexpected safety signals emerged. Infusion-related reactions were common on infusion day 1 but were not observed on infusion day 2 • Phase 2 MIRROR trial has not reported results • Phase 3 ASCLEPIOS I trial has not reported results

Ozanimod • Orally administered, nonselective S1P • In the phase 2 RADIANCE trial, mean cumulative number of receptor modulator being studied in RRMS Gd-enhancing lesions (weeks 12-24), number of Gd-enhancing • Penetrates BBB, and binds S1P1R and S1P5R lesions (week 24), and new/enlarging T2 lesions (weeks 12-24) • Safety profile appears to be superior to that of were decreased significantly with both doses of ozanimod (0.5 other S1P agents mg and 1 mg) versus placebo. The most commonly reported • Receptor selectivity, PK properties, and use of AEs with ozanimod included nasopharyngitis, headache, and dose escalation potentially differentiate the urinary tract infection. ECGs and 24-hour Holter monitoring cardiac profile of ozanimod from that of other demonstrated no increased incidence of atrioventricular block or S1P agents sinus pause with ozanimod • Phase 3 SUNBEAM trial has not reported results

Ponesimod • Orally administered, selective S1P1 receptor • In a phase 2b trial, mean cumulative number of new T1 modulator being studied in RRMS Gd-enhancing lesions (weeks 12-24) was significantly lower • Penetrates BBB and binds S1P1R with all ponesimod doses (10 mg, 20 mg, and 40 mg) versus placebo. Additionally, mean ARRs were lower with ponesimod 40 mg versus placebo. The most commonly reported AEs with ponesimod included anxiety, dizziness, dyspnea, increased alanine aminotransferase, influenza, insomnia, and peripheral edema • Phase 3 OPTIMUM trial has not reported results

Siponimod • Orally administered, selective S1P receptor • In a phase 2 trial in RRMS, a dose-response relation modulator being studied in RRMS and SPMS was observed (P = .0001) across the 5 doses of siponimod, • Penetrates BBB, and binds S1P1R and S1P5R with reductions in combined unique active lesions at 3 months compared with placebo. Common AEs included headache, bradycardia, dizziness, and infections of the nose and throat • In a phase 3 trial in SPMS, siponimod significantly reduced confirmed disability progression by 21% versus placebo (P = .013). Common AEs included headache, nasopharyngitis, urinary tract infection, falls, and hypertension

AE indicates adverse event; ARR, annualized relapse rate; BBB, blood–brain barrier; ECG, electrocardiogram; Gd, gadolinium; LFT, liver function tests; MOA, mechanism of action; MS, multiple sclerosis; PK, pharmacokinetics; PPMS, primary progressive MS; RRMS, relapsing-remitting MS; S1P, sphingosine-1-phosphate; S1P1R, S1P receptor 1; S1P5R, S1P receptor 5; SPMS, secondary progressive MS.

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The relationship between the mechanism of action of or deductible amounts to restrictive insurance barriers, prior DMTs and subsequent therapies should be evalu- which can negatively affect patient care.5 ated.4 In some cases, previous DMTs could potentially nullify or attenuate the mode of action of future therapies. Unmet Needs The T-cell– and B-cell–depleting actions of alemtuzumab Although the currently approved DMTs are reliable, and ocrelizumab, respectively, occur immediately following constantly being improved, effective in treating relapses, the use of fingolimod if lymphocytes have not yet exited and capable of decreasing long-term disability, they have from secondary lymphoid tissue. only limited efficacy for the treatment of progressive The development of PML has been associated with the disease without the occurrence of additional inflammatory use of several DMTs.4 The risk differs according to DMT. relapses.6 In fact, of all the currently approved DMTs, only 1 Natalizumab is associated with the highest risk for PML (inci- agent—ocrelizumab—has been approved for the treatment dence, 1/100 to 1/1000), followed by fingolimod (incidence, of patients with primary progressive MS.27 1/18,000) and dimethyl fumarate (incidence, approximately Because the neuroarchitectural damage that occurs 1/50,000).4 The risk for PML with other DMTs is either very during relapses accumulates over time and is associated low or unclear. It is currently not known whether or how the with increasing patient disability, neuroprotective and sequencing of DMTs might affect overall PML risks. regenerative therapies are needed.6 Specifically, agents It is generally recommended that live vaccinations be that repair or regenerate neurons, oligodendrocytes, and avoided in patients with MS.1,4 The prescribing information supporting glia are critical components of the MS treat- for teriflunomide, fingolimod, daclizumab*, and alemtu- ment armamentarium.7 zumab advise against the use of live attenuated vaccines Limiting disability among patients with MS will inevi- during and for prespecified time periods after discontin- tably require a multidimensional approach that targets uing therapy.20-23 both the peripheral and the central nervous systems, Aside from glatiramer acetate and the interferon beta focusing on specific immune components, as well as on agents, all of other DMTs have been associated with a risk those pathways that are thought to contribute significantly for infection, including both community-acquired infections to neurodegenerative processes.28 and opportunistic infections.24 Patients should therefore be screened for latent viruses and other conditions (such as The MS Pipeline hepatitis B infections) prior to initiating therapy. As noted earlier, several new medications are being inves- tigated in late-phase clinical studies for the treatment The High Cost of DMTs of patients with relapsing or progressive forms of MS.8 MS is a disabling, chronic disease that imposes a substantial These agents represent a variety of mechanisms of action, economic burden on both patients and on the US health- and are associated with lower relapse rates and improve- care system.5 The single largest driver of MS-associated ments in disabilities. Several of these pipeline agents healthcare expenditures are prescription drugs, which are selective sphingosine-1-phosphate (S1P) receptor account for more than half of all direct medical costs. In immunomodulators, including laquinimod, ozanimod, particular, the costs of DMTs have risen dramatically over ponesimod, and siponimod. These agents have similar the last 10 years.5 The price of some of these medications efficacy to the currently approved S1P immunomodu- has increased nearly 10-fold (see Table 1). Acquisition costs lator fingolimod, whereas ozanimod appears to have an for nearly all DMTs currently exceed $70,000 per year.5 This improved safety profile compared with other drugs in its does not include costs incurred from the care of patients class.8 Ofatumumab is a CD20-positive B-cell–targeting receiving these agents (such as laboratory monitoring, first- monoclonal antibody, and masitinib is a mast-cell inhib- dose observation period, and physician visits), only the cost itor.8 Phase 3 trials for some of these agents will conclude of the actual DMT itself. within the next 12 months, and their manufacturers are It is important to note that patients with MS often expected to apply for FDA approval soon thereafter. Table 2 require many medications in addition to DMTs. Use of describes a variety of agents in the MS pipeline. these medications is responsible for additional costs in the healthcare system. Conclusions Generic formulations are available for both the glat- In addition to efficacy and safety concerns, clinicians must iramer acetate 20 mg and 40 mg formulations.25,26 also consider the optimal time to initiate MS therapy, adher- Fingolimod will lose exclusivity in 2019; it is anticipated ence factors, switching strategies, and cost issues when that generic competition will occur soon thereafter. prescribing DMTs to patients.2-5 These considerations are a The high cost of DMTs has a cascade of negative conse- reflection of the many unmet needs of the MS care spec- quences for patients, ranging from excessive cost-sharing trum. With more agents in the pipeline offering the potential

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to lower relapse rates and improve disabilities, however, the docs/HOM/Exp_Consensus.pdf. Accessed February 9, 2018. treatment landscape is poised for continued growth, giving 18. Farber RS, Sand IK. Optimizing the initial choice and timing of therapy in relaps- clinicians increased opportunities to possibly improve treating-remitting multiple sclerosis. Ther Adv Neurol Disord. 2015;8(5):212-232. ment outcomes as well as quality of life. 19. Goldenberg MM. Multiple sclerosis review. P T. 2012;37(3):175-184. 20. Aubagio [package insert]. Cambridge, MA: Genzyme Corporation; November 2016. 21. Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; * In March 2018, Biogen withdrew daclizumab (Zinbryta) December 2017. worldwide following reports of inflammatory encephalitis 22. Zinbryta [package insert]. Cambridge, MA: Biogen Inc; August 2017. and meningoencephalitis. 23. Lemtrada [package insert]. Cambridge, MA: Genzyme Corporation; December 2017. 24. 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